SUMMARY Sepsis is a medical condition caused by an overwhelming systemic inflammatory response to infection. Although the underlying infection can now be efficiently treated with antibiotics, there are no effective therapies to control the organ damage caused by the inflammatory response of the host. As a result, sepsis is the leading cause of mortality in intensive care units and is the tenth leading cause of death overall in the US. The ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) CD39 is a cell surface-associated anti- inflammatory enzyme. It has multiple anti-inflammatory actions, which include degradation of the endogenous proinflammatory molecule adenosine triphosphate and triggering of the production of the anti-inflammatory agent adenosine. We have discovered that endogenous CD39 protects mice against polymicrobial sepsis- induced mortality, organ damage, and inflammation. Similarly, injecting a soluble E-NTPDase/CD39 mimic (apyrase) is protective. Based on these results, we propose exogenously administered soluble E-NTPDase as a novel and effective therapy for sepsis. However, apyrase, an E-NTPDase/CD39 mimic of plant origin, is likely to provoke a hazardous antibody response in humans preventing its use as a therapeutic agent for septic patients. To overcome this problem, in the current proposal we will evaluate the effect of an optimized human recombinant soluble E-NTPDase (APT102) in sepsis. Our hypothesis is that APT102 would reduce mortality, organ injury, and inflammation in sepsis. To address this hypothesis, we propose two Specific Aims. In Specific Aim 1, we will test the efficacy of APT102 in preventing mortality in polymicrobial sepsis induced by cecal ligation and puncture in mice. In Specific Aim 2, we will delineate the effect of APT102 on organ injury and inflammation in sepsis. We expect that APT102 will reduce mortality, organ injury, and inflammation in septic mice. The long-term goal of this study is to develop APT102 as a safe and effective treatment option for the management of patients with sepsis.